Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

Table 2 The Dynamic Changes Occurring in the Immune Microenvironment after EGFR Inhibition in an EGFR-Mutant Transgenic Mouse Model

Effect of EGFR-TKIs on tumor immune Microenvironment	Early Treatment	Later Treatment	Throughout Treatment
Antitumor Activity	Tumor burden↓	Tumor burden↓	Tumor burden↓
Antitumor Activity	Tumor size↓	Tumor size↓	Tumor size↓
Expression of Immune Checkpoint Molecules	PD-L1↓^a	PD-L1↓^a	PD-L1↓^a
	PD-1↓^b	PD-1↓^b	PD-1↓^b
	CTLA-4↓^b	CTLA-4↓ ^b	CTLA-4↓^b
	TIM-3↓^b	TIM-3↓^b	TIM-3↓^b
Lymphocyte Infiltration	CD3+ lymphocytes ↑	CD3+ lymphocytes +/−
	CD8+ T cells↑	CD8+ T cells
	Foxp3+ Tregs↓	Foxp3+ Tregs
Macrophage Infiltration	CD11b + Myeloid Cells↑	CD11b + Myeloid Cells↑	CD11b + Myeloid Cells↑
	PMN-MDSCs +/−	PMN-MDSCs +/−	PMN-MDSCs +/−
	M-MDSCs↑	M-MDSCs↑	M-MDSCs↑
	DCs↑	DCs+/−
	M1-TAM↑	M1-TAM↓
	M2-TAM↓	M2-TAM↓	M2-TAM↓
Cytokine Secretion	IL-10 +/−	IL-10↑
Cytokine Secretion	CCL-2 +/−	CCL-2↑

PD-L1 Programmed death-ligand 1, PD-1 Programmed cell death protein 1, CTLA-4 The cytotoxic T-lymphocyte–associated antigen 4, TIM-3 T-cell immunoglobulin and mucin-domain containing-3, PMN-MDSCs Polymorphonuclear MDSCs, M-MDSCs Mononuclear MDSCs, IL-10 Interleukin 10, CCL-2 The chemokine (C- C motif) ligand 2
^a: PD-L1 expression after EGFR-TKI monotherapy in both CD45+ immune cells and CD4 − tumor cells;
^b: PD-1, CTLA-4, and TIM-3 expression on CD3+ lymphocytes;
+/−: Remained unchanged
↑: increased
↓: decreased

ISSN: 1476-4598